Emerging Role of Garcinol in Targeting Cancer Stem Cells of Non-small Cell Lung Cancer

  • Liang Wang
  • Meiyan WangEmail author
  • Hongxing Guo
  • Hui Zhao
Natural Products: From Chemistry to Pharmacology (C Ho, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Natural Products: From Chemistry to Pharmacology
  2. Topical Collection on Natural Products: From Chemistry to Pharmacology


Garcinol is a polyisoprenylated benzophenone analogue primarily isolated from the dried rind of Garcinia indica, a tropical fruit widely grown in Southeast Asia and Central Africa. Recent findings have well documented that garcinol is a potential dietary phytochemical candidate in the prevention and treatment of cancer and oxidative-related illness. Herein, a brief structure-activity relationship (SAR) is summarized in this review to disclose the connection between the chemical structure of garcinol and its biological activity. Non-small cell lung cancer (NSCLC) is a predominant type of lung cancer, exhibiting an extremely high mortality rate as a result of failing to clean up cancer stem cells (CSCs). Interestingly, garcinol was reported to be able to target and suppress CSCs, and both in vitro and in vivo evidences have revealed the outstanding anti-NSCLC potential of garcinol. The mechanism may involve cellular senescence and apoptosis induction, as well as cell cycle arrest. This paper will review the current progress of garcinol against various tumors in vitro and in vivo, particularly the effects on NSCLC, and summarize the critical structural features of garcinol as a potent anticancer candidate. Also, we will discuss potential future challenges in research and development of garcinol.


Garcinol Structure-activity relationship Anticancer Non-small cell lung cancer Cancer stem cells 


Funding Information

This study received support from the National Natural Science Foundation of China (grant numbers 31571832 and 81803548), Key Program of Tianjin Municipal Health Bureau (grant number 2013-GG-05), and Tianjin Innovative Research Team Grant (grant number TD-13-5087), and Open Grant from Tianjin Key Laboratory of Food Biotechnology (TJCU-KLFB-18201).

Compliance with Ethical Standards

Conflict of Interest

The authors declare no conflicts of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.


  1. 1.
    Torre LA, Siegel RL, Ward EM, Jemal A. Global cancer incidence and mortality rates and trends--an update. Cancer Epidemiol Biomark Prev. 2016;25(1):16–27.CrossRefGoogle Scholar
  2. 2.
    Torre LA, Bray F, RL Siegel J, Ferlay J, Lortet-Tieulent AJ. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65(2):87–108.CrossRefGoogle Scholar
  3. 3.
    Hu Y, Fu L. Targeting cancer stem cells: a new therapy to cure cancer patients. Am J Cancer Res. 2012;2(3):340–56.Google Scholar
  4. 4.
    Khan S, Karmokar A, Howells L, Thomas AL, Bayliss R, Gescher A, et al. Targeting cancer stem-like cells using dietary-derived agents - where are we now? Mol Nutr Food Res. 2016;60(6):1295–309.CrossRefGoogle Scholar
  5. 5.
    Dandawate PR, Subramaniam D, Jensen RA, Anant S. Targeting cancer stem cells and signaling pathways by phytochemicals: novel approach for breast cancer therapy. Semin Cancer Biol. 2016;40-41:192–208.CrossRefGoogle Scholar
  6. 6.
    Knobloch TJ, Uhrig LK, Pearl DK, Casto BC, Warner BM, Clinton SK, et al. Suppression of proinflammatory and prosurvival biomarkers in oral cancer patients consuming a black raspberry phytochemical-rich troche. Cancer Prev Res (Phila). 2016;9(2):159–71.CrossRefGoogle Scholar
  7. 7.
    Marventano S, Salomone F, Godos J, Pluchinotta F, Del Rio D, Mistretta A, et al. Coffee and tea consumption in relation with non-alcoholic fatty liver and metabolic syndrome: a systematic review and meta-analysis of observational studies. Clin Nutr. 2016;35(6):1269–81.CrossRefGoogle Scholar
  8. 8.
    Braakhuis AJ, Campion P, Bishop KS. Reducing breast cancer recurrence: the role of dietary polyphenolics. Nutrients. 2016;8(9).Google Scholar
  9. 9.
    Yamaguchi F, Ariga T, Yoshimura Y, Nakazawa H. Antioxidative and anti-glycation activity of garcinol from Garcinia indica fruit rind. J Agric Food Chem. 2000;48(2):180–5.CrossRefGoogle Scholar
  10. 10.
    Krishnamurthy N, Lewis YS, Ravindranath B. On the structures of garcinol, isogarcinol and camboginol. Tetrahedron Lett. 1981;22(8):793–6.CrossRefGoogle Scholar
  11. 11.
    Krishnamurthy N, Ravindranath B, TNG Row KV. Crystal and molecular structure of isogarcinol. Tetrahedron Lett. 1982;23(21):2233–6.CrossRefGoogle Scholar
  12. 12.
    Sahu A, Das B, Chatterjee A. Polyisoprenylated benzophenones from Garcinia pedunculata. Phytochemistry. 1989;28(4):1233–5.CrossRefGoogle Scholar
  13. 13.
    Liu C, Ho PC, Wong FC, Sethi G, Wang LZ, Goh BC. Garcinol: current status of its anti-oxidative, anti-inflammatory and anti-cancer effects. Cancer Lett. 2015;362(1):8–14.CrossRefGoogle Scholar
  14. 14.
    Choudhury B, Kandimalla R, Elancheran R, Bharali R, Kotoky J. Garcinia morella fruit, a promising source of antioxidant and anti-inflammatory agents induces breast cancer cell death via triggering apoptotic pathway. Biomed Pharmacother. 2018;103:562–73.CrossRefGoogle Scholar
  15. 15.
    Li F, Shanmugam MK, Siveen KS, Wang F, Ong TH, Loo SY, et al. Garcinol sensitizes human head and neck carcinoma to cisplatin in a xenograft mouse model despite downregulation of proliferative biomarkers. Oncotarget. 2015;6(7):5147–63.Google Scholar
  16. 16.
    Parasramka MA, Ali S, Banerjee S, Deryavoush T, Sarkar FH, Gupta S. Garcinol sensitizes human pancreatic adenocarcinoma cells to gemcitabine in association with microRNA signatures. Mol Nutr Food Res. 2013;57(2):235–48.CrossRefGoogle Scholar
  17. 17.
    Hatcher H, Planalp R, Cho J, Torti FM, Torti SV. Curcumin: from ancient medicine to current clinical trials. Cell Mol Life Sci. 2008;65(11):1631–52.CrossRefGoogle Scholar
  18. 18.
    Chen X, Zhang X, Y L, JY Shim S, Sang ZS, et al. Chemoprevention of 7,12-dimethylbenz[a]anthracene (DMBA)-induced hamster cheek pouch carcinogenesis by a 5-lipoxygenase inhibitor, garcinol. Nutr Cancer. 2012;64(8):1211–8.CrossRefGoogle Scholar
  19. 19.
    Li N, Sood S, Wang S, Fang M, Wang P, Sun Z, et al. Overexpression of 5-lipoxygenase and cyclooxygenase 2 in hamster and human oral cancer and chemopreventive effects of zileuton and celecoxib. Clin Cancer Res. 2005;11(5):2089–96.CrossRefGoogle Scholar
  20. 20.
    Han CM, XY Zhou JC, Zhang XY, Chen X. 13,14-Dihydroxy groups are critical for the anti-cancer effects of garcinol. Bioorg Chem. 2015;60:123–9.CrossRefGoogle Scholar
  21. 21.
    Robert T, Vanoli F, Chiolo I, Shubassi G, Bernstein KA, Rothstein R, et al. HDACs link the DNA damage response, processing of double-strand breaks and autophagy. Nature. 2011;471(7336):74–9.CrossRefGoogle Scholar
  22. 22.
    Ganai SA, Banday S, Farooq Z, Altaf M. Modulating epigenetic HAT activity for reinstating acetylation homeostasis: a promising therapeutic strategy for neurological disorders. Pharmacol Ther. 2016;166:106–22.CrossRefGoogle Scholar
  23. 23.
    Li T, Zhang C, Hassan S, Liu X, Song F, Chen K, et al. Histone deacetylase 6 in cancer. J Hematol Oncol. 2018;11(1):111.CrossRefGoogle Scholar
  24. 24.
    Rouaux C, Jokic N, Mbebi C, Boutillier S, Loeffler JP, Boutillier AL. Critical loss of CBP/p300 histone acetylase activity by caspase-6 during neurodegeneration. EMBO J. 2003;22(24):6537–49.CrossRefGoogle Scholar
  25. 25.
    Yan G, MS Eller CE, Larocca CA, Ryu B, Panova IP, et al. Selective inhibition of p300 HAT blocks cell cycle progression, induces cellular senescence, and inhibits the DNA damage response in melanoma cells. J Invest Dermatol. 2013;133(10):2444–52.CrossRefGoogle Scholar
  26. 26.
    Balasubramanyam K, Altaf M, Varier RA, Swaminathan V, Ravindran A, Sadhale PP, et al. Polyisoprenylated benzophenone, garcinol, a natural histone acetyltransferase inhibitor, represses chromatin transcription and alters global gene expression. J Biol Chem. 2004;279(32):33716–26.CrossRefGoogle Scholar
  27. 27.
    Mantelingu K, Reddy BA, Swaminathan V, Kishore AH, Siddappa NB, Kumar GV, et al. Specific inhibition of p300-HAT alters global gene expression and represses HIV replication. Chem Biol. 2007;14(6):645–57.CrossRefGoogle Scholar
  28. 28.
    Arif M, Pradhan SK, Thanuja GR, Vedamurthy BM, Agrawal S, Dasgupta D, et al. Mechanism of p300 specific histone acetyltransferase inhibition by small molecules. J Med Chem. 2009;52(2):267–77.CrossRefGoogle Scholar
  29. 29.
    Sang S, Liao CH, Pan MH, Rosen RT, Lin-Shiau SY, Lin JK, et al. Chemical studies on antioxidant mechanism of garcinol: analysis of radical reaction products of garcinol with peroxyl radicals and their antitumor activities. Tetrahedron. 2002;57(50):9931–8.CrossRefGoogle Scholar
  30. 30.
    Zhou XY, Cao J, Han CM, Li SW, Zhang C, YD D, et al. The C8 side chain is one of the key functional group of Garcinol for its anti-cancer effects. Bioorg Chem. 2017;71:74–80.CrossRefGoogle Scholar
  31. 31.
    Padhye S, Ahmad A, Oswal N, Dandawate P, Rub RA, Deshpande J, et al. Fluorinated 2′-hydroxychalcones as garcinol analogs with enhanced antioxidant and anticancer activities. Bioorg Med Chem Lett. 2010;20(19):5818–21.CrossRefGoogle Scholar
  32. 32.
    Milite C, Feoli A, Sasaki K, La Pietra V, Balzano AL, Marinelli L, et al. A novel cell-permeable, selective, and noncompetitive inhibitor of KAT3 histone acetyltransferases from a combined molecular pruning/classical isosterism approach. J Med Chem. 2015;58(6):2779–98.CrossRefGoogle Scholar
  33. 33.
    Wang YW, Zhang X, Chen CL, Liu QZ, Xu JW, Qian QQ, et al. Protective effects of Garcinol against neuropathic pain - evidence from in vivo and in vitro studies. Neurosci Lett. 2017;647:85–90.CrossRefGoogle Scholar
  34. 34.
    Hong J, Sang S, Park HJ, Kwon SJ, Suh N, Huang MT, et al. Modulation of arachidonic acid metabolism and nitric oxide synthesis by garcinol and its derivatives. Carcinogenesis. 2006;27(2):278–86.CrossRefGoogle Scholar
  35. 35.
    Stark TD, Salger M, Frank O, Balemba OB, Wakamatsu J, Hofmann T. Antioxidative compounds from Garcinia buchananii stem bark. J Nat Prod. 2015;78(2):234–40.CrossRefGoogle Scholar
  36. 36.
    Wang Y, Tsai ML, Chiou LY, Ho CT, Pan MH. Antitumor activity of Garcinol in human prostate cancer cells and xenograft mice. J Agric Food Chem. 2015;63(41):9047–52.CrossRefGoogle Scholar
  37. 37.
    Rakoff-Nahoum S. Why cancer and inflammation? Yale J Biol Med. 2006;79(3–4):123–30.Google Scholar
  38. 38.
    Scott TL, Rangaswamy S, Wicker CA, Izumi T. Repair of oxidative DNA damage and cancer: recent progress in DNA base excision repair. Antioxid Redox Sign. 2014;20(4):708–26.CrossRefGoogle Scholar
  39. 39.
    Yamaguchi F, Saito M, Ariga T, Yoshimura Y, Nakazawa H. Free radical scavenging activity and antiulcer activity of garcinol from Garcinia indica fruit rind. J Agric Food Chem. 2000;48(6):2320–5.CrossRefGoogle Scholar
  40. 40.
    Cooke MS, Evans MD, Dizdaroglu M, Lunec J. Oxidative DNA damage: mechanisms, mutation, and disease. FASEB J. 2003;17(10):1195–214.CrossRefGoogle Scholar
  41. 41.
    Ziaei S, Halaby R. Immunosuppressive, anti-inflammatory and anti-cancer properties of triptolide: a mini review. Avicenna J Phytomed. 2016;6(2):149–64.Google Scholar
  42. 42.
    Li S, Wang H, Guo L, Zhao H, Ho CT. Chemistry and bioactivity of nobiletin and its metabolites. J Funct Foods. 2014;6(1):2–10.CrossRefGoogle Scholar
  43. 43.
    Ahmad A, SH Sarkar A, Aboukameel S, Ali B, Biersack SS, et al. Anticancer action of garcinol in vitro and in vivo is in part mediated through inhibition of STAT-3 signaling. Carcinogenesis. 2012;33(12):2450–6.CrossRefGoogle Scholar
  44. 44.
    Oike T, Ogiwara H, Torikai K, Nakano T, Yokota J, Kohno T. Garcinol, a histone acetyltransferase inhibitor, radiosensitizes cancer cells by inhibiting non-homologous end joining. Int J Radiat Oncol Biol Phys. 2012;84(3):815–21.CrossRefGoogle Scholar
  45. 45.
    Yu SY, Liao CH, Chien MH, Tsai TY, Lin JK, Weng MS. Induction of p21(Waf1/Cip1) by garcinol via downregulation of p38-MAPK signaling in p53-independent H1299 lung cancer. J Agric Food Chem. 2014;62(9):2085–95.CrossRefGoogle Scholar
  46. 46.
    Kaur J, Tikoo K. p300/CBP dependent hyperacetylation of histone potentiates anticancer activity of gefitinib nanoparticles. Biochim Biophys Acta. 2013;1833(5):1028–40.CrossRefGoogle Scholar
  47. 47.
    Wang J, Wang L, Ho CT, Zhang K, Liu Q, Zhao H. Garcinol from Garcinia indica downregulates cancer stem-like cell biomarker ALDH1A1 in nonsmall cell lung cancer A549 cells through DDIT3 activation. J Agric Food Chem. 2017;65(18):3675–83.CrossRefGoogle Scholar
  48. 48.
    Huang WC, Kuo KT, Adebayo BO, Wang CH, Chen YJ, Jin K, et al. Garcinol inhibits cancer stem cell-like phenotype via suppression of the Wnt/beta-catenin/STAT3 axis signalling pathway in human non-small cell lung carcinomas. J Nutr Biochem. 2018;54:140–50.CrossRefGoogle Scholar
  49. 49.
    Zhang L, Wen X, Li M, Li S, Zhao H. Targeting cancer stem cells and signaling pathways by resveratrol and pterostilbene. Biofactors. 2018;44(1):61–8.CrossRefGoogle Scholar
  50. 50.
    Takebe N, Harris PJ, Warren RQ, Ivy SP. Targeting cancer stem cells by inhibiting Wnt, Notch, and Hedgehog pathways. Nat Rev Clin Oncol. 2011;8(2):97–106.CrossRefGoogle Scholar
  51. 51.
    Yu H, Kortylewski M, Pardoll D. Crosstalk between cancer and immune cells: role of STAT3 in the tumour microenvironment. Nat Rev Immunol. 2007;7(1):41–51.CrossRefGoogle Scholar
  52. 52.
    Ho YS, Chen CH, Wang YJ, Pestell RG, Albanese C, Chen RJ, et al. Tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) induces cell proliferation in normal human bronchial epithelial cells through NFkappaB activation and cyclin D1 up-regulation. Toxicol Appl Pharmacol. 2005;205(2):133–48.CrossRefGoogle Scholar
  53. 53.
    Wu CH, Lee CH, Ho YS. Nicotinic acetylcholine receptor-based blockade: applications of molecular targets for cancer therapy. Clin Cancer Res. 2011;17(11):3533–41.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Liang Wang
    • 1
  • Meiyan Wang
    • 1
    Email author
  • Hongxing Guo
    • 2
  • Hui Zhao
    • 1
  1. 1.Tianjin Key Laboratory of Food and Biotechnology, Food Science Division, School of Biotechnology and Food ScienceTianjin University of CommerceTianjinPeople’s Republic of China
  2. 2.Department of BiotherapyThird Central Hospital of Tianjin Medical UniversityTianjinChina

Personalised recommendations